Fibroproliferative processes are a group of disorders characterized by an excessive proliferation of mesenchymal fibroblast-like spindle cells. They range from hypertrophic wounds to the development of neoplasms such as aggressive fibromatosis (AF).
During wound healing, several cell types and signaling pathways are activated to reconstitute the epithelial and dermis layers of the skin. Following cutaneous injury, three sequentially distinct but overlapping processes are initiated: inflammatory, proliferation, and remodeling. During the proliferative phase, mesenchymal fibroblast-like cells accumulate in the dermal component of the skin while the epithelial cell barrier layer is reformed (Singer 1999, Martin 1997, McClain 1996). β-catenin has been shown to mediate epithelial and mesenchymal cell activity, whereby it is able to increase proliferation and differentiation in dermal mesenchymal cells and decrease migration in epithelial keratinocytes (Cheon 2002). Mouse models have demonstrated that β-catenin can modulate the resulting wound size, where induced levels of β-catenin by lithium treatment result in wound healing with a larger size (Cheon 2006). Also, a transgenic mouse in which stabilized β-catenin is expressed in mesenchymal cells, has been generated, under control of a tetracycline-regulated promoter. Wounded mice healed with hyperplastic cutaneous wounds compared to wildtype control mice (Cheon 2002). This demonstrates the importance of β-catenin in mesenchymal cells and its crucial role in wound healing.
Another fibroproliferative disorder mediated by β-catenin is aggressive fibromatosis (AF), also called desmoid tumour. AF is a locally invasive soft tissue tumour comprised of mesenchymal fibroblast-like spindle cells. AF occurs as either a sporadic lesion or a familial syndrome, such as familial adenomatous polyposis (FAP). B-catenin stabilization is a universal occurrence in AF, as demonstrated by elevated β-catenin levels and increase β-catenin-mediated transcriptional activity. Furthermore, β-catenin stabilization is sufficient to cause AF as shown using a transgenic mouse model that over-expresses the stabilized form of β-catenin (Cheon 2002). This suggests a crucial role β-catenin plays in fibroproliferative disorders and its importance in mesenchymal cells.
In addition to a role for β-catenin in fibroproliferative disorders, a number of studies have demonstrated deregulated β-catenin expression is an important event in the genesis of a number of malignancies, such as colon cancer, melanoma, hepatocellular carcinoma, ovarian cancer, endometrial cancer, medulloblastoma pilomatricomas, and prostate cancer. β-catenin mutations appear to be a crucial step in the progression of a subset of these cancers, suggesting an important role in the control of cellular proliferation or cell death (as described in Polakis P. The many ways of Wnt in cancer. Curr Opin Genet Dev. 2007 February; 17(1):45-51).
In view of foregoing, it is desirable to develop novel methods effective to treat conditions and disorders that may be associated with β-catenin.